This invention relates to magnetic resonance imaging (MRI), also referred to as nuclear magnetic resonance (NMR) imaging, and more particularly, to methods and compositions for enhancing magnetic resonance images of body organs and tissues.
The recently developed techniques of MRI or NMR imaging encompasses the detection of certain atomic nuclei utilizing magnetic-fields and radio-frequency radiation. It is similar in some respects to x-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. In current use, the images produced constitute a map of the distribution density of protons and/or their relaxation times in organs and tissues. The MRI technique is advantageously non-invasive as it avoids the use of ionizing radiation.
While the phenomenon of NMR was discovered in 1945, it is only relatively recently that it has found application as a means of mapping the internal structure of the body as a result of the original suggestion of Lauterbur (Nature, 242, 190-191, 1973). The lack of any known hazard associated with the level of the magnetic and radio-frequency fields that are employed renders it possible to make repeated scans on vulnerable individuals. Additionally, any scan plane can readily be selected including transverse, coronal, and sagittal sections.
In an NMR experiment, the nuclei under study in a sample (e.g., protons) are irradiated with the appropriate radio-frequency (RF) energy in a highly uniform magnetic field. These nuclei as they relax subsequently emit RF radiation at a sharp resonant frequency. The emitted frequency (RF) of the nuclei depends on the applied magnetic field.
According to known principles, nuclei with appropriate spin when placed in an applied magnetic field [B, expressed generally in units of gauss or tesla (104 gauss)] align in the direction of the field. In the case of protons, these nuclei precess at a frequency f=42.6 MHz at a field strength of 1 Tesla. At this frequency, an RF pulse of radiation will excite the nuclei and can be considered to tip the nuclei out of the field direction, the extent of this rotation being determined by the pulse duration and energy. After the RF pulse, the nuclei xe2x80x9crelaxxe2x80x9d or return to equilibrium with the magnetic field, emitting radiation at the resonant frequency. The decay of the signal is characterized by two relaxation times, i.e., T1, the spin-lattice relaxation time or longitudinal relaxation time, that is, time taken by the nuclei to return to equilibrium along the direction of the externally applied magnetic field, and T2, the spin-spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins. These relaxation times have been established for various fluids, organs and tissues in different species of mammals.
In MRI, scanning planes and slice thickness can be selected without loss of resolution. This permits high quality transverse, coronal and sagittal images to be obtained directly. The absence of any moving parts in MRI equipment promotes a high reliability. It is believed that MRI or NMR imaging has a greater potential than CT for the selective examination of tissue characteristics in view of the fact that in CT, x-ray attenuation coefficients alone determine image contrast whereas at least four separate variables (T1, T2, nuclear spin density and flow) may contribute to the NMR signal. For example, it has been shown (Damadian, Science, 171, 1151, 1971) that the values of the T1 and T2 relaxation in tissues are generally longer by about a factor of 2 in excised specimens of neoplastic tissue compared with the host tissue.
By reason of its sensitivity to subtle physio-chemical differences between organs and/or tissues, it is believed that MRI may be capable of differentiating tissue types and in detecting diseases which induce physio-chemical changes that may not be detected by x-ray or CT which are only sensitive to differences in the electron density of tissue. The images obtainable by MRI techniques also enable the physician to detect structures smaller than those detectable by CT and thereby provide comparable or better spatial resolution.
N-substituted iminodiacetic acids, such as methyliminodiacetic acid (MIDA) and N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid (HIDA), labeled with technetium xe2x88x9299m, cobalt-57 and other radiometals have been used as radio-pharmaceutical imaging agents for the liver or hepatobiliary system. In this regard, reference is made to U. S. Pat. Nos. 4,308,249, 4,316,883, 4,318,898, 4,350,674 and 4,418,208 and to J. Nucl. Med. 17:633-638 (1976) and J. Nucl. Med. 17(6), 545 (1976).
Among the several objects of the invention may be noted the provision of novel compositions for enhancing magnetic resonance images of body organs and tissues; the provision of such compositions which contain a substantially non-toxic manganese complex of certain N-(dialkylphenylcarbamoylmethyl)iminodiacetic acid compounds; and the provision of methods for enhancing magnetic resonance images of body organs and tissues through the administration of such compositions. Other objects and features will be in part apparent and in part pointed out hereinafter.
Briefly, the invention is directed to compositions for enhancing magnetic resonance images of body organs and tissues, the composition comprising a substantially nontoxic manganese complex of a compound of the formula: 
wherein n=0, 1 or 2, R1 and R2 are hydrogen or alkyl groups of 1 to 4 carbon atoms, and R3 and R4 are hydrogen, alkyl groups of 1 to 4 carbon atoms or halogen. The invention is also directed to methods for enhancing magnetic resonance images of body organs and tissues by administering such compositions to a mammal in sufficient amounts to provide enhancement of magnetic resonance images of the body organs and tissues.
In accordance with the present invention, it has now been found that magnetic resonance images of body organs and tissues may be usefully enhanced through the administration to a mammal of a substantially nontoxic manganese complex of a compound of the formula: 
wherein n=0, 1 or 2, R1 and R2 are hydrogen or alkyl groups of 1 to 4 carbon atoms, and R3 and R4 are hydrogen, alkyl groups of 1 to 4 carbon atoms or halogen.
Manganese is a paramagnetic element capable of altering or enhancing magnetic resonance images, i.e. it is capable of altering the magnetic resonance signal characteristics of body tissues, organs or fluids and thus aid in differentiating normal from diseased tissue. Administered as a free ionic salt (e.g. chloride), it may also exhibit some target organ specificity (e.g. liver). However, such paramagnetic salts or compounds may undesirably exhibit significant toxicity.
In accordance with the present invention, we have found that manganese complexes of the above-noted compounds are relatively or substantially nontoxic and are therefore useful for enhancing magnetic resonance images by favorably altering relaxation times T1 and T2 and thereby affording improved contrast between normal and diseased tissues or organs. Illustrative manganese complexes of the aforementioned class of compounds which may be used in carrying out the invention include manganese complexes of N-[Nxe2x80x2-(2,6-diisopropylphenylcarbamoylmethyl]iminodiacetic acid, N-[Nxe2x80x2-(2,6-diethyl-4,5-dimethylphenyl)carbamoylmethyl]iminodiacetic acid, N-[Nxe2x80x2-(2,6-dimethyl-4,5-difluorophenyl)carbamoylmethyl]iminodiacetic acid, N-[Nxe2x80x2-(4-fluoro-2,5,6-trimethylphenyl)carbamoylmethyl]iminodiacetic acid and N-[Nxe2x80x2-(5-bromo-2,4,6-trimethylphenyl)carbamoylmethyl]iminodiacetic acid. Compounds of the aforementioned formula wherein n is 0 are preferred. The manganese complexes of the invention may be in the form of mono-, dior trihydrates.
As shown by the toxicity studies set forth hereinafter, a representative member of the class of manganese complexes herein contemplated, namely, dihydrogen bis(N-[Nxe2x80x2-(2,6-dimethylphenyl)carbamoylmethyl]iminodiaceto)-manganese(II) trihydrate, possesses a favorable intravenous toxicity profile and dramatically reduces hepatic and biliary T1 relaxation times. In contrast, a gadolinium complex of the same class, namely, hydrogen bis(N-[Nxe2x80x2-(2,6-dimethylphenyl)carbamoylmethyl]iminodiaceto)gadolinium(III) dihydrate, possesses a relatively poor toxicity profile (LD50 of about 0.2 mmol/kg with persistent, delayed toxicity) and also has relatively poor T1 and T2 lowering effects in the liver.
The substantially nontoxic manganese complexes of the present invention are administered to a mammal in a sufficient amount to provide enhancement of magnetic resonance images of body organs and tissues prior to obtaining a magnetic resonance scan or scans of such organs and tissues with xe2x80x9cslicesxe2x80x9d being taken at the level of the desired organ at various time periods post-administration.